Cigarette smoking is the major environmental risk factor for the development of chronic obstructive pulmonary disease (COPD); however, only a subset of smokers develop clinically significant COPD. In addition to the risk from smoking, subjects with severe alpha 1-antitrypsin deficiency have a major genetic predisposition to COPD; other genetic determinants of COPD have not been proven. The frequent development of COPD in individuals with alpha 1-antitrypsin deficiency has provided a foundation for the protease-antiprotease hypothesis for the pathogenesis of COPD. However, many subjects with severe, early-onset COPD are not alpha 1-antitrypsin deficient. To define the mechanisms responsible for the development of severe, early-onset COPD unrelated to alpha 1-antitrypsin deficiency, we propose a multidisciplinary study that combines field, laboratory, and analytical approaches. We will assemble a group of 140 pedigrees ascertained through probands with severe, early-onset COPD (without severe alpha 1-antitrypsin deficiency) who are referred for lung transplant or lung volume reduction surgery evaluations. We will assess these probands and their relatives with spirometry (including bronchodilator response) and a questionnaire. We will obtain genotyping with highly polymorphic short tandem repeat (STR) markers at 10 cM intervals throughout the genome from the NHLBI Mammalian Genotyping Service; these genotypes will be used to assess for genetic linkage to phenotypes including FEV1, FEV1/FVC, chronic bronchitis, and bronchodilator responsiveness. In chromosomal regions with suggestive linkage from the genome screen, additional STR markers will be tested at 1 cM intervals; multipoint linkage analysis, family-based association studies, and haplotype analysis will be used to narrow the regions likely to contain genetic determinants of COPD-related phenotypes. mRNA levels of genes within these regions narrowed by fine mapping will be compared in lung tissue from early-onset COPD probands and control subjects. The results of this study could identify specific regions of the genome which are likely to contain COPD susceptibility genes and provide candidate susceptibility genes for COPD. Identification of such genetic determinants could provide insight into the biochemical mechanisms causing the variable development of COPD at all ages, allow identification of highly susceptible individuals, and lead to new therapeutic interventions for COPD.